Abstract: One half of cancer patients in the United States receive radiation therapy at sometime during the course of disease. Existing radiation therapy of cancer using external x-ray beam relies on free radicals generated from water radiolysis to damage DNA, and the selectivity of tumor killing is due to diminished ability of cancer cells to repair damaged DNA. A great challenge of external beam x-ray radiation therapy is that high dose radiations damage surrounding healthy tissues. Although many techniques have been used to enhance radiosensitivity of tumor, and minimize x-ray doses on normal cells, at time when radiation dose is sufficient to kill tumor, damage to normal cells already occurs. The low tumor selectivity limit radiation dose that can be safely administered to such an extent that incomplete treatment or recurrence of cancer occurs frequently. Instead of generating DNA-damaging free radicals outside cancer cells, or inside both cancer and normal cells, this project is to develop a new nanoparticle enhanced x-ray radiation therapy modality, in which complex oxide nanoparticles that are specifically attached at cancer cells are used as nanoscale frequency convertors to convert highly penetrating x-ray into fluorescence in ultraviolet region; the internally produced fluorescence can cause chemical reactions of photoactive molecules immobilized on nanoparticles, and change the surface properties of nanoparticles so that nanoparticles can penetrate cellular and nuclear membranes; subsequent x- ray irradiation can generate free radicals around nanoparticles inside nuclei of cancer cells to damage DNAs. If successful, this new cancer treatment method could dramatically enhance the survivability of cancer patients especially those with buried cancers by providing effective treatments at low radiation doses. In a much larger context, this particular submission is the cornerstone to establish an entirely new research area, In-vivo Photochemistry, in which functional nanoparticles that are delivered at certain site inside the body will be used as nanoscale frequency modulators to convert high frequency highly penetrating x-ray radiation into low frequency ultraviolet or visible light emission that can be absorbed by photoactive organic molecules at nanoparticle surface or inside cells. This new use of functional nanoparticles removes the long-lasting obstacle of low tissue penetration depth of ultraviolet and visible lights, and allows many photochemical reactions to be able to carry out inside the body. By providing an unprecedented control at molecular, cellular, or tissue level, this project will have a far-reaching and profound impact on wide variety of biomedical fields including cancer treatment, neural signal control and drug releasing, among many others. Public Health Relevance: The new use of nanoparticles as nanoscale frequency modulator removes the long-lasting obstacle of low tissue penetration depth of ultraviolet and visible light, allows many photochemical reactions to be carried out inside body, and will have a profound impact on a wide variety of biomedical fields. The x-ray radiation therapy with nanoparticles internalized into nuclei of cancer cells represents a paradigm shift from existing radiation therapy. This method could significantly enhance effectiveness of x-ray radiation therapy, and reduce damage to normal cells, and thus dramatically enhance the survivability and quality of life of cancer patients.